Method and composition for treating cns disorders

ABSTRACT

Compositions and methods for treating a range of Central Nervous System (CNS) disorders and diseases such as amyloidosis, protein folding diseases, tauopathy, and specifically Alzheimer&#39;s Disease and Parkinson&#39;s Disease, among others, in humans and in veterinary animals, by administering to a subject in need thereof a formulation comprising of melatonin, curcumin and cannabis, specifically THC alone or with CBD.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority on prior U.S. ProvisionalApplication Ser. No. 62/650,942, filed Mar. 30, 2018, which is herebyincorporated herein in its entirety by reference.

This invention relates to compositions and methods for treating a rangeof Central Nervous System (CNS) disorders and diseases such asamyloidosis, protein folding diseases, tauopathy, and specifically forexample Alzheimer's Disease (AD) and Parkinson's Disease (PD), amongothers, in humans and animals using a formulation comprising of acombination of a cannabis compound, or compounds, melatonin, andturmeric.

BACKGROUND ALZHEIMER'S DISEASE (AD)

About 45 million suffer from Alzheimer's Disease (“AD”) worldwide. Theestimated economic burden in 2017 was over $200 billion for AD relatedservices. By 2050, an estimated 11 to 16 million Americans will beliving with the disease. Several clinical trials had indicated thatcombination therapy has greater efficacy over monotherapy. (Alzheimer's,Assn, 2012 Alzheimer's disease facts and figures. Alzheimer's Dement.2012; 8: 131-168; Brookmeyer, et al, Forecasting the global burden ofAlzheimer's disease. Alzheimer's Dement. 2007; 3: 186-191; Schitt et al,CNS Drugs 2004; 18:827-844).

AD poses an enormous burden on caregivers, as well as the health caresystem. About 30 percent of the cost of treating AD is the cost of caregivers. Currently, there is no cure for AD. (Saxena, Bioenergeticsbreakdown in Alzheimer's disease: Targets for new therapies. Int JPhysiol Pathophysiol Pharmacol. 2011; 3: 133-139; Götz, et al., Modes ofAβ toxicity in Alzheimer's disease. Cell Mol Life Sci. 2011; 68:3359-3375).

AD pathology can be grouped into two forms, familial inherited AD, andsporadic AD. The pathologies of early onset familial AD and late onsetsporadic AD are indistinguishable. The two forms of AD are characterizedby extracellular amyloid-β (Aβ) peptide plaque deposits, and bytau-containing neurofibrillary tangles (Götz, et al., Modes of Aβtoxicity in Alzheimer's disease. Cell Mol Life Sci. 2011; 68:3359-3375).

The misfolded structure of the Aβ peptides, alongside withneurofibrillary tangles, makes a characteristic tendency for theiraggregation around damaged or dead neurons and within cerebralvasculature in the brain. It establishes by memory loss followed byadvanced AD. (Chili & Dobson, Protein misfolding, functional amyloid,and human disease. Annu Rev Biochem. 2006; 75: 333-366).

It has long been agreed that Aβ1-40 (Aβ40) and Aβ1-42 (Aβ42) aggregatesare the constituents of the insoluble plaques that are characteristic ofAD. This disease is also accompanied with neuro-inflammation,excitotoxicity, and oxidative stress. (Campbell & Gowran, Alzheimer'sdisease; taking the edge off with cannabinoids? Br J Pharmacol. 2007;152: 655-662; Rich, et al., Nonsteroidal anti-inflammatory drugs inAlzheimer's disease. Neurology. 1995; 45: 51-55). However, thecontinuous aggregation of Aβ peptides along with hyper-phosphorylationof tau protein inside the cell, producing neurofibrillary tangleformation, are generally recognized as the major etiological factors ofthe neuronal cell death associated with the evolution of AD (Octave, Theamyloid peptide and its precursor in Alzheimer's disease. Rev Neurosci.1995; 6: 287-316; Reitz, et al., Epidemiology of Alzheimer disease. NatRev Neurol. 2011; 7: 137-152; Pillay, et al., Molecular mechanisms,emerging etiological insights and models to test potential therapeuticinterventions in Alzheimer's disease. Curr Alzheimer Res. 2004; 1:295-306).

The studies show that Aβ peptides are neurotoxic, as they are reportedintermediaries of apoptosis, inflammation, and oxidative stress. Forthis purpose, some of the initial proposed therapeutic strategiesinvolve the prevention or elimination of these Aβ peptides and followingformation of toxic oligomers. Aβ peptides are produced via theamyloidogenic pathway of amyloid precursor protein (APP) proteolysis,which involves the combined effort of β- and γ-secretases. Initially,β-secretase (BACE) cleaves APP, creating an Aβ-containingcarboxyl-terminal fragment known as β-C-terminal fragment (β-CTF), orC99 and an amino-terminal, soluble APP-β (sAPP-β) fragment, which isreleased extracellularly. Intracellularly, the β-CTF fragment is thencleaved by a multiprotein γ-secretase complex, resulting in productionof the Aβ peptide and a smaller γ-CTF, also known as C57. Aβ is known tosurge: cellular Ca²⁺, mitochondrial progression of the diseasecondition.

Prior studies have also suggested that glycogen synthase kinase 3(GSK-3) has a key role in the pathogenesis of both sporadic and familialAD (Hooper, et al., The GSK3 hypothesis of Alzheimer's disease. JNeurochem. 2008; 104: 1433-1439; Proctor & Gray, GSK3 and p53—is there alink in Alzheimer's disease? Mol Neurodegener. 2010; 5: 7).

It has been demonstrated that GSK-3β induces hyperphosphorylation oftau. (Lovestone, et al., Alzheimer's disease-like phosphorylation of themicrotubule-associated protein tau by glycogen synthase kinase-3 intransfected mammalian cells. Curr Biol. 1994; 4: 1077-1086;

Ishiguro, et al., Phosphorylation sites on tau by tau protein kinase I,a bovine derived kinase generating an epitope of paired helicalfilaments. Neurosci Lett. 1992; 148: 202-206;

Hanger, et al., Glycogen synthase kinase-3 induces Alzheimer'sdisease-like phosphorylation of tau: Generation of paired helicalfilament epitopes and neuronal localization of the kinase. NeurosciLett. 1992; 147: 58-62;

Cho & Johnson, Glycogen synthase kinase 3beta phosphorylates tau at bothprimed and unprimed sites. Differential impact on microtubule binding. JBiol Chem. 2003; 278: 187-193;

Asuni, et al., GSK3alpha exhibits beta-catenin and tau directed kinaseactivities that are modulated by Wnt In. Eur J Neurosci. 2006; 24:3387-3392).

Furthermore, over expression of GSK-3 in Tet/GSK-3β mice exhibitpathological symptoms that parallel AD pathology with respect to spatiallearning deficits, reactive astrocytosis, increased Aβ production, andplaque associated inflammation, as well as tau hyperphosphorylationresulting in Aβ-mediated neuronal death (Hernandez, et al., GSK3 andtau: Two convergence points in Alzheimer's disease. J Alzheimers Dis.2013; 33(Suppl 1): S141-S144).

Moreover, chronic lithium (GSK-3 inhibitor) usage in transgenic miceover expressing GSK-3β and tau has shown to check tauhyperphosphorylation and neurofibrillary tangle formation (Engel, etal., Chronic lithium administration to FTDP-17 tau and GSK-3beta overexpressing mice checks tau hyperphosphorylation and neurofibrillarytangle formation, but pre-formed neurofibrillary tangles do not revert.J Neurochem. 2006; 99: 1445-1455). Some reports have also demonstratedthat GSK-3α plays a role in regulating amyloid-β protein precursor(AβPPP) cleavage, resulting in increased Aβ production (Phiel, et al.,(2003) GSK-3alpha controls production of Alzheimer's diseaseamyloid-beta peptides. Nature. 2003; 423: 435-439; Sun, et al., Lithiuminhibits amyloid secretion in COS7 cells transfected with amyloidprecursor protein C100. Neurosci Lett. 2002; 321: 61-64).

It has also been discovered that the Aβ load in mouse brain can bestrongly decreased by the inhibition of GSK-3β (DaRocha-Souto, et al.,Activation of glycogen synthase kinase-3 beta mediates beta-amyloidinduced neuritic damage in Alzheimer's disease. Neurobiol Dis. 2012; 45:425-437).

Along with prior research suggesting an involvement of GSK-3 in thepathogenesis of AD, there has also been recent studies indicating theintricate participation of the cannabinoid system in AD. It was reportedthat the cannabinoid system can limit the neurodegenerative processesthat drive the progression of the disease, and may provide a newpossibility for disease control (Jackson, et al., Cannabinoids andneuroprotection in CNS inflammatory disease. J Neurol Sci. 2005; 233:21-25).

Currently, the complete pathway and mechanism of action of thecannabinoid system are not clear, however, studies have been performedto determine the involvement of the cannabinoid 1 (CB1) and cannabinoid2 (CB2) receptors in AD brain (Campbell & Gowran, Alzheimer's disease;taking the edge off with cannabinoids? Br J Pharmacol. 2007; 152:655-662). The CB1 receptor is rich in the brain and contributes tolearning, memory, and cognitive processes which are interrupted early inthe onset of AD. (Riedel & Davies, Cannabinoid function in learning,memory and plasticity. Handb Exp Pharmacol. 2005; 445-477). While, CB2receptor expression is more limited and has been anatomically found inneurons within the brainstem (Van Sickle, et al., Identification andfunctional characterization of brainstem cannabinoid CB2 receptors.Science. 2005; 310: 329-332), cerebellum (Ashton, et al., Expression ofthe cannabinoid CB2 receptor in the rat cerebellum: Animmunohistochemical study. Neurosci Lett. 2006; 396: 113-116), andmicroglia (Nunez, et al., Cannabinoid CB2 receptors are expressed byperivascular microglial cells in the human brain: An immunohistochemicalstudy. Synapse. 2004; 53: 208-213).

Recent research has also examined the propensity of endocannabinoidreceptor sub-types 1 (CB1) and 2 (CB2) to elicit a neuroprotective andanti-inflammatory effects on the brain when stimulated byendocannabinoids (Marchalant, et al., Cannabinoids attenuate the effectsof aging upon neuroinflammation and neurogenesis. Neurobiol Dis. 2009;34: 300-307). An increased expression of CB1 and CB2 receptors onmicroglia within the plaque, while CB1 expression is reduced in neuronsmore remote from the plaque in the postmortem brains of AD patients(Ramirez, et al., Prevention of Alzheimer's disease pathology bycannabinoids: Neuroprotection mediated by blockade of microglialactivation. J Neurosci. 2005; 25: 1904-1913).

The endocannabinoid metabolizing enzyme, fatty acid amide hydrolase, isupregulated in the plaque in AD brains (Benito, et al., Cannabinoid CB2receptors and fatty acid amide hydrolase are selectively overexpressedin neuritic plaque-associated glia in Alzheimer's disease brains. JNeurosci. 2003; 23: 11136-11141). There is also an increase in levels ofanandamide metabolites, such as arachidonic acid, in the vicinity of theplaque (Benito, et al., Cannabinoid CB2 receptors and fatty acid amidehydrolase are selectively overexpressed in neuritic plaque-associatedglia in Alzheimer's disease brains. J Neurosci. 2003; 23: 11136-11141).These findings may indirectly suggest that the increase in CB1 and CB2receptors may be to counterbalance the lack of activity with theirligands due to increased metabolic activity of fatty acid amidehydrolase.

These changes in the cannabinoid system suggest an involvement ofendogenous cannabinoids in the pathogenesis of AD or that this systemmay be altered by the pathophysiology of the disease (Campbell & Gowran,Alzheimer's disease; taking the edge off with cannabinoids? Br JPharmacol. 2007; 152: 655-662). Understanding that microglial activationis unaffected in all cases of AD, it is important to identify thatendogenous cannabinoids stop Aβ-induced microglial activation both invitro and in vivo models (Martín-Moreno, et al., Cannabidiol and othercannabinoids reduce microglial activation in vitro and in vivo:Relevance to Alzheimer's disease. Mol Pharmacol. 2011; 79: 964-973).These receptors are known to experience time-dependent and brain regionspecific changes during neurodegenerative and neuroinflammatorydisorders to try to respond excitotoxicity and inflammation (Bisogno &Di Marzo, Cannabinoid receptors and endocannabinoids: Role inneuroinflammatory and neurodegenerative disorders. CNS Neurol DisordDrug Targets. 2010; 9: 564-573).

BACKGROUND: EFFECT OF THC ON AD BIOMARKERS AND SYMPTOMS

Endocannabinoid receptors, CB1 and CB2, have been confirmed to interactwith the endocannabinoid molecules: 2-arachidonoyl glycerol andanandamide. However, it has also been stated that CB1 and CB2 also reactinteract with Δ⁹-tetrahydrocannabinol (THC) an ingredient from theCannabis sativa plant (Piomelli, The molecular logic of endocannabinoidsignaling. Nat Rev Neurosci. 2003; 4: 873-884). Furthermore, earlyreports show that Dronabinol, an oil-based solution of Δ9-THC, improvesthe disturbed behavior and stimulates appetite in AD patients (Volicer,et al., Effects of dronabinol on anorexia and disturbed behavior inpatients with Alzheimer's disease. Int J Geriatr Psychiatry. 1997; 12:913-919). THC possesses antioxidant, anti-inflammatory andneuroprotective properties (Jackson, et al., Cannabinoids andneuroprotection in CNS inflammatory disease. J Neurol Sci. 2005; 233:21-25).

In the year 2006, Eubanks and et al, demonstrated that THC competitivelyinhibits the enzyme acetylcholinesterase (AChE) as well as prevents AChEinduced amyloid beta-peptide (Abeta) aggregation. The concentration ofTHC used was 50 micromolar at the cellular level (Eubanks L m, Rogers CJ, Beuscher A E 4^(th), Koob G F, Olson A J, Dickerson T J, Janda K D. Amolecular link between the active component of marijuana and Alzheimer'sdisease pathology. Mol Pharm. 2006 November-December 3(6): 773-7).

Several studies have shown that cannabis ingestion, specifically THC,causes acute psychotic reactions, anxiety, impaired neuropsychologicalperformance, impaired memory, executive functioning disorder,mitochondrial dysfunction, neuron apoptosis, and severe side effectssuch as feeling high, anxiety, depression, among others. (Morrison P D1, Zois V, McKeown D A, Lee T D, Holt D W, Powell J F, Kapur S, Murray RM. Morrison P D 1, Zois V, McKeown D A, Lee T D, Holt D W, Powell J F,Kapur S, Murray R M. Epub 2009 Apr. 1). The acute effects of syntheticintravenous Delta9-tetrahydrocannabinol on psychosis, mood and cognitivefunctioning.

BACKGROUND: EFFECT OF MELATONIN ON AD BIOMARKERS AND SYMPTOMS

Melatonin (N-acetyl-5-methoxytryptamine), a tryptophan metabolite andsynthesized mainly in the pineal gland and plays an important role inregulation of many physiological functions. This include regulatingcircadian rhythms, clearing free radicals, improving immunity andgenerally inhibiting the oxidation of biomolecules. Studies have showndecreased levels of melatonin in serum and cerebrospinal fluid (CSF) ofAD patients. (The human pineal gland and melatonin in aging andAlzheimer's disease. J. Pineal Res. 2005; 38:145-152; Wu Y. H., FeenstraM. G., Zhou J. N., Liu R. Y., Torano J. S., van Kan H. J., Fischer D.F., Ravid R., Swaab D. F. Molecular changes underlying reduced pinealmelatonin levels in Alzheimer's disease: Alterations in preclinical andclinical stages. J. Clin. Endocr. Metab. 2003; 88:5898-5906.).

Clinical studies have indicated that melatonin supplementation has beenshown to improve circadian rhythmicity, for example, decreasing agitatedbehavior, confusion and “sundowning”, and to produce beneficial effectson memory in AD patients (Cohen-Mansfield J., Garfinkel D., Lipson S.Melatonin for treatment of sundowning in elderly persons with dementia—Apreliminary study. Arch. Gerontol. Geriatr. 2000; 31:65-76; Cardinali D.P., Brusco L. I., Perez Lloret S., Furio A. M. Melatonin in sleepdisorders and jet-lag. Neuro Endocrinol. Lett. 2002; 23:9-13.

Melatonin supplementation poses low toxicity and may be one of thepossible strategies for symptomatic treatment. (Karasek M., Reiter R.J., Cardinali D. P., Pawlikowski M. Future of melatonin as a therapeuticagent. Neuro Endocrinol. Lett. 2002; 23:118-121.; 23. Singer C.,Tractenberg R. E., Kaye J., Schafer K., Gamst A., Grundman M., ThomasR., Thal L. J. Alzheimer's disease cooperative, SA multicenter,placebo-controlled trial of melatonin for sleep disturbance inAlzheimer's disease. Sleep. 2003; 26:893-901.

Several studies have reported that ingestion of Melatonin has sideeffects such as causes headache, dizziness, nausea, drowsinessdepression, anxiety, tremor, camps, irritability, confusion,hypotension, among others. (Nordlund J J, Lerner A B. The effects oforal melatonin on skin color and on the release of pituitary hormones, JClin Endocrinol Metab. 1977; 45: 768-774; 140. Papvasiliou P S, CotziasG C, Duby S E, Steck A J, Bell M, Lawrence W H. Melatonin andparkinsonism [letter]. JAMA. 1972; 221: 88).

BACKGROUND: EFFECT OF CURCUMIN ON AD BIOMARKERS AND SYMPTOMS

Curcumin is a polyphenolic natural compound derived from the rootCurcuma longa or turmeric. Several studies have demonstrated thatcurcumin possess a properties of anti-carcinogenic, anti-inflammatoryand anti-oxidative properties (Goel A, Kunnumakkara A B, Aggarwal B B.Curcumin as “Curecumin”: from kitchen to clinic. Biochem Pharmacol. 2008Feb. 15; 75(4):787-809). Curcumin has been reported to binds to Aβprotein and prevents the aggregation of Aβ in-vitro studies (Maiti P andDunbar G L. Use of Curcumin, a Natural Polyphenol for TargetingMolecular Pathways in Treating Age-Related Neurodegenerative DiseasesInt J Mol Sci. 2018 May 31; 19(6)). Several pre-clinical studies havereported that curcumin has possess an anti-amyloidogenic property byinhibiting formation of amyloid beta oligomers and fibrils, bindsplaques in animal models of AD (Koronyo-Hamaoui M, Koronyo Y, Ljubimov AV, Miller C A, Ko M K, Black K L, Schwartz M, Farkas D L. Identificationof amyloid plaques in retinas from Alzheimer's patients and noninvasivein vivo optical imaging of retinal plaques in a mouse model. Neuroimage.2011 January; 54 Suppl 1( ):S204-17; Maiti P, Hall T C, Paladugu L,Kolli N, Learman C, Rossignol J, Dunbar G L. A comparative study ofdietary curcumin, nanocurcumin, and other classical amyloid-binding dyesfor labeling and imaging of amyloid plaques in brain tissue of5×-familial Alzheimer's disease mice. Histochem Cell Biol. 2016November; 146(5):609-625; Maiti P, Paladugu L, Dunbar G L. Solid lipidcurcumin particles provide greater anti-amyloid, anti-inflammatory andneuroprotective effects than curcumin in the 5×FAD mouse model ofAlzheimer's disease. BMC Neurosci. 2018 Feb. 23; 19(1):7). Curcumin hasbeen shown to binds to neurofibrillary tangles in AD brain tissue(Mohorko N, Repovs G, Popović M, Kovacs G C, Bresjanac M. Curcuminlabeling of neuronal fibrillar tau inclusions in human brain samples. JNeuropathol Exp Neurol. 2010 April; 69(4):405-14; Mutsuga M, Chambers JK, Uchida K, Tei M, Makibuchi T, Mizorogi T, Takashima A, Nakayama H. ofcurcumin to senile plaques and cerebral amyloid angiopathy in the agedbrain of various animals and to neurofibrillary tangles in Alzheimer'sbrain. J Vet Med Sci. 2012 January; 74(1):51-7)

Studies have reported that curcumin can decrease the level of Aβ-inducedincreases in reactive oxygen species, curcumin can also enhancedecreases in mitochondrial membrane potential, and activates or inhibitscaspase, a protein that is intimately involved in the regulation ofapoptosis activation, as well as defend human neurons from oligomeric Aβinduced toxicity (Mishra, et al., 2011) It is also reported thatcannabinoids are active against inflammation (Mishra S, Mishra M, SethP, Sharma S K. Tetrahydrocurcumin confers protection against amyloidβ-induced toxicity. Neuroreport. 2011 Jan. 5; 22(1):23-7).

A small double-blind, placebo-controlled 18-Month trial reported thatdaily oral theracurmin (90 mg) treatment lead to improved memory andattention and a reduction in brain amyloid and tau levels in nondementedadults (Small et al., Memory and Brain Amyloid and Tau Effects of aBioavailable Form of Curcumin in Non-Demented Adults: A Double-Blind,Placebo-Controlled 18-Month Trial, Am J Geriatr Psychiatry. 2018 March;26(3):266-277).

It is well established that AD is complex chronic disease arising fromalterations in various signaling pathways. Several hypotheses have beenput forward and investigated in AD pathology including beta amyloidpathology, inflammation, neurodegeneration and oxidative stress,hyperphosphorylation of tau, mitochondrial cascade, prion, and so on.Targeting one hypothesis has failed to provide protection against AD.Several studies have demonstrated that monotherapy has limited efficacyas compared to polytherapy. Polytherapy involves two or more activeingredients which target key signaling pathways.

Several studies have reported that ingestion of curcumin has sideeffects such as rash, yellow stool, among others. (Lao C. D., Ruffin M.T., Normolle D., Heath D. D., Murray S. I., Bailey J. M., Boggs M. E.,Crowell J., Rock C. L., Brenner D. E. Dose escalation of a curcuminoidformulation. BMC Complement. Altern. Med. 2006; 6: 10 doi:10.1186/1472-6882-6-10).

SUMMARY

The invention provides methods and compositions for treating centralnervous system (CNS) disorders in humans and animals which involvestreating a patient with a CNS disorder such as Alzheimer's disease orParkinson's disease with a composition including (i)tetrahydrocannabinol (THC) in a dose amount per 70 kg patient of fromabout 14 μg to about 10.0 mg, preferably in an ultra-low dose per 70 kgpatient of from about 14 μg to about 2.0 mg; (ii) melatonin in a doseamount per 70 kg patient of from about 1.4 mg to about 20.0 mg; and(iii) curcumin in a dose amount per 70 kg patient of about 0.35 mg toabout 500 mg.

In a preferred embodiment, cannabidiol (CBD) in a dose amount per 70 kgpatient of from about 14 μg to about 200 mg is administered to a patientalong with THC, melatonin and curcumin in the dose amounts specifiedherein or with THC and melatonin without curcumin. These formulationsare preferred for treating Parkinson's disease. In a further embodiment,a composition for treating central nervous system (CNS) disorders inhumans and animals includes: (i) tetrahydrocannabinol (THC) in anultra-low dose amount per 70 kg patient of from about 14 μg to about 2.0mg; and (ii) cannabidiol (CBD) in a dose amount per 70 kg patient offrom about 14{tilde over ( )}g mg to about 200 mg. Another compositionfor treating central nervous system (CNS) disorders in humans andanimals includes: (i) cannabidiol (CBD) in a dose amount per 70 kgpatient of from about 14{tilde over ( )}g mg to about 200 mg; and (ii)melatonin in a dose amount per 70 kg patient of from about 1.4 mg toabout 20.0 mg. Additional compositions comprise THC or CBD each withcurcumin in the dose amounts disclosed herein without melatonin. Thecompositions and methods for treating central nervous system (CNS)disorders and diseases such as amyloidosis, protein folding diseases,tauopathy, and specifically for example Alzheimer's Disease andParkinson's Disease among others, in humans and in veterinary animalsare effective to reduce Aβ expression; reduce Aβ aggregation; maintainAPP expression; enhance mitochondrial functioning; decreasephosphorylation of GSK3β protein; decrease the expression of GSK3βprotein; decrease phosphorylation of tau protein; reduce anxiety; reduceagitation; reduce sleep disorder, and/or reduce care giver distress,without severe side effects associated with high doses of THC, CBDmelatonin and/or high doses of curcumin.

In another preferred embodiment the compositions of the invention areadministered orally in a liquid carrier which includes a non-ionicemulsifier in an amount sufficient to maintain stability and solubilityof the formulation. Suitable non-ionic emulsifiers include lecithin fromsoy or sunflower, polysorbate 80) and vitamin E TPGS (d-α-tocopherylpolyethylene glycol 1000 succinate). Natural anti-fungal agents such asrutin are also preferred to maintain stability.

DESCRIPTION

The invention provides a method and compositions for treating centralnervous system (CNS) disorders in humans and animals which involvestreating a patient with a CNS disorder such as Alzheimer's orParkinson's with a composition including (i) tetrahydrocannabinol (THC)in an ultra-low dose amount per 70 kg patient of from about 14 μg toabout 2.0 mg without severe psychological impairments and side effectsassociated with higher doses of THC; (ii) melatonin in a dose amount per70 kg patient of from about 14 μg to about 77.0 mg; and (iii) curcuminin a dose amount per 70 kg patient of about 7 mg to about 100 mg.

In a preferred embodiment, cannabidiol (CBD) in a dose amount per 70 kgpatient of from about 14 μg to about 100 mg is administered to a patientalong with THC, melatonin and curcumin.

In another preferred embodiment the composition of the invention isadministered orally in a liquid carrier which includes a non-ionicemulsifier in an amount sufficient to maintain stability and solubilityof the composition components. Suitable non-ionic emulsifiers includelecithin from soy or sunflower, Tween 80 (polysorbate 80), and vitamin ETPGS (d-α-tocopheryl polyethylene glycol 1000 succinate).

This invention provides a method for treating certain CNS disorders andsymptoms, and diseases classified broadly as amyloidosis, proteinfolding diseases, tauopathy, and specifically for example Alzheimer'sDisease (AD), among others, in humans and veterinary animals whichincludes administering to a subject in need thereof a compositionincluding (i) an effective amount of melatonin, (ii) an effective amountof curcumin and (iii) a cannabis compound containing THC in a microdosage amount that is sufficient to provide efficacy while not inducingside effects commonly associated with cannabis, melatonin or curcumin.

Compositions of the invention for treating Alzheimer's and related CNSdiseases in humans and veterinary animals include: (i) an effectiveamount of melatonin, (ii) an effective amount of curcumin and (iii) acannabis compound containing THC in an amount that is sufficient toprovide efficacy while not inducing side effects commonly associatedwith cannabis, melatonin or curcumin. The composition is administeredorally in a suitable carrier.

Compositions of the invention for treating Alzheimer's and related CNSdiseases in humans and veterinary animals include: (i) an effectiveamount of melatonin, (ii) an effective amount of curcumin (iii) acannabis compound containing THC, and (iv) a cannabis compoundcontaining CBD, in an amount that is sufficient to provide efficacywhile not inducing side effects commonly associated with cannabis,melatonin or curcumin. The composition is administered orally in asuitable carrier.

Compositions of the invention for treating Alzheimer's and related CNSdiseases in humans and veterinary animals include: (i) an effectiveamount of melatonin, (ii) an effective amount of curcumin and (iii) acannabis compound containing CBD, in an amount that is sufficient toprovide efficacy while not inducing side effects commonly associatedwith cannabis, melatonin or curcumin. The composition is administeredorally in a suitable carrier.

Compositions of the invention for treating Alzheimer's and related CNSdiseases in humans and veterinary animals include: (i) an effectiveamount of melatonin, and (ii) an effective amount of curcumin in anamount that is sufficient to provide efficacy while not inducing sideeffects commonly associated with higher doses of melatonin and curcumin.The composition is administered orally in a suitable carrier.

Cannabis compounds can be synthetic (chemically synthesized) orextracted from cannabis plants such as sativa, indica, hemp or hybridstrains of sativa and indica. A preferred source of tetrahydrocannabinol(THC) is so-called organic THC, which is extracted from cannabis andcontains minor amounts of other cannabinoids such as CBD. Full spectrumcannabis oil, full spectrum hemp oil and full spectrum marijuana areextracted from hemp

This invention provides a method for treating certain disorders,symptoms, and diseases classified broadly as amyloidosis, proteinfolding diseases, tauopathy, and specifically for example Alzheimer'sDisease (AD), among others, in mammals by administering to a subject inneed thereof a composition including: (i) an effective amount ofmelatonin, (ii) an effective amount of curcumin and (iii) a cannabiscompound in an amount that is sufficient to provide efficacy while notinducing side effects commonly associated with cannabis.

A preferred 1 ml oral suspension for a 70-kg human is administered oncea day, twice a day, thrice a day or four times a day depending on theseverity of the symptoms and comprises up to 2.5 mg of THC, up to 1.5 mgof melatonin, and up to 0.5 mg curcumin.

A preferred 1 ml oral suspension for a 70-kg human is administered oncea day, twice a day, thrice a day or four times a day depending on theseverity of the symptoms and comprises up to 2.5 mg of THC, up to 1.5 mgof melatonin and up to 200 mg CBD.

Dose ranges for the components of the inventive composition follow.

THC is administered with the other inventive components in dose amountsas follows:

Per kg of patient weight: from about 0.2 μg to about 0.14 mgPer 70 kg patient: from about 14 μg to about 10 mgPreferred per kg of patient weight: from about 0.2 μg to about 0.03 mg.Preferred per 70 kg patient: from about 14 μg to about 2.0 mg.

Melatonin is administered with the other inventive components in doseamounts as follows:

Per kg of patient weight: from about 0.02 mg to about 0.3 mg.Per 70 kg patient: from about 1.4 mg to about 20 mg.Preferred per kg of patient weight: from about 0.01 mg to about 0.15 mg.Preferred per 70 kg patient: from about 0.7 mg to about 10 mg.

CBD is administered with the other inventive components in dose amountsas follows:

Per kg of patient weight: from about 0.2 μg to about 3.0 mg.Per 70 kg patient: from about 14 μg to about 200 mg.Preferred per kg of patient weight: from about 0.03 mg to about 3.0 mg.Preferred per 70 kg patient: from about 2.0 mg to about 200 mg.Also preferred per kg of patient weight: from about 0.02 μg to about0.036 mg.Also preferred per 70 kg patient: from about 14 μg to about 2.5 mg.

Curcumin is administered with the other inventive components in doseamounts as follows:

Per kg of patient weight: from about 0.005 mg to about 7.0 mg.Per 70 kg patient: from about 0.35 mg to about 500 mg.Preferred per kg of patient weight: from about 0.01 mg to about 3.5 mg.Preferred per 70 kg patient: from about 0.7 mg to about 250 mg.

The preferred oral dose is in the range of 1 ml of an oral suspension,for a 70-Kg human, once a day, twice a day, thrice a day or four times aday depending on the severity of the symptoms comprising of a cannabiscompound with up to 2.5 mg of THC, but less than the amount which causespsychological impairments and side effects associated with higher dosesof THC, up to 1.5 mg of melatonin, and up to 0.5 mg curcumin.

A preferred 1 ml oral suspension, for a 70-Kg human, once a day, twice aday, thrice a day or four times a day depending on the severity of thesymptoms comprises THC in the range from about 14 μg to about 10 mg,melatonin in the range from about 0.02 mg to about 0.3 mg, curcumin inthe range from about 0.35 mg to about 500 mg and CBD in the range fromabout 14 μg to about 200 mg, but with THC, less than the amount whichcauses psychological impairments and side effects associated with higherdoses of THC, melatonin, curcumin and CBD.

The preferred oral dose is in the range of 1 ml of an oral suspension,for a 70-Kg human, once a day, twice a day, thrice a day or four times aday depending on the severity of the symptoms comprising of THC in therange shown in Table 1, CBD in the range shown in Table 1 but with THC,less than the amount which causes psychological impairments and sideeffects associated with higher doses of THC, and CBD.

The combination of melatonin, curcumin, and cannabis is believed to workalong several pathways in controlling various end points and thehallmarks of Alzheimer's Disease as well as diseases classified broadlyas amyloidosis, protein folding diseases, and/or tauopathy. It isbelieved that the dosing in the formulation does not cause any of theside effects commonly associated with cannabis, melatonin or turmeric.The dosing of cannabis prescribed in the formulation herein is below the5 mg levels prescribed by the FDA for Dronabinol and well below the 50micromolar level used in the Eubanks 2006 study (Eubanks L m, Rogers CJ, Beuscher A E 4^(th), Koob G F, Olson A J, Dickerson T J, Janda K D. Amolecular link between the active component of marijuana and Alzheimer'sdisease pathology, Mol Pharm. 2006 November-December 3(6): 773-7). Usingtime-release formulations for any of the components, can further enhancebioavailability.

The combination of lower dose of melatonin, curcumin, cannabis compoundsunexpectedly leads to (i) a reduction of side effects, such astransient, acute psychotic reactions, anxiety, impairedneuropsychological performance, memory impairments, executivefunctioning disorder, mitochondrial dysfunction, and (ii) other sideeffects like headache, dizziness, nausea, drowsiness, depression,anxiety, tremor, camps, irritability, confusion, hypotension, rash,yellow stool, among others, otherwise present with higher doses ofmelatonin, curcumin and cannabis compounds, or when each of melatonin,curcumin and or cannabis is used alone.

Suitable pharmaceutically acceptable cannabis compounds include cannabisextract, which includes phytocannabinoids such as tetrahydrocannabinol“THC” (9-Tetrahydrocannabinol (delta-9 THC), 8-tetrahydrocannabinol(Delta-8 THC) and 9-THC Acid), cannabidiol (CBD), otherphytocannabinoids such as cannabinol (CBN), cannabichromene (CBC),cannabigerol (CBG) among others, terpenoids and flavonoids. Standardizedcannabis extract (SCE) consists of mostly THC, CBD and CBN. Organic THCconsists of solvent extracted THC from cannabis with lesser or traceamounts of other cannabinoids and terpenoids. Synthetic or pure THC isfree of CBD and other compounds is a preferred cannabis compound.

THC and CBD can be extracted from a cannabis indica dominant strainusing, for example, high pressure and carbon dioxide or ethanol as asolvent in a 1500-20 L subcritical/supercritical CO2 system made byApeks Super Critical Systems, 14381 Blamer Rd., Johnstown, Ohio, 43031.

The cannabis plant in its natural form contains THCA. The resin calledshatter is extracted from the cannabis flower using any of a variety ofmethods including CO2 extraction as described herein. Shatter isproduced using a three-step process: kief separation, extraction, andwinterization. Cannabis flower is introduced into a steel tumbler over amesh sieve with dry ice. Flower is frozen and broken while tumbled withdry ice chunks allowing fine THCA bearing particles (kief) to fallthrough the sieve. THCA is then extracted from kief using supercriticalextraction. A solvent such as CO2 and kief are introduced into achamber. That sealed chamber is pressurized to approximately 2800 psiand heated to 53 degrees C. Supercritical CO2 is then allowed to flowout of the pressurized chamber into a vile at room temperature andpressure (while more CO2 is introduced to maintain pressure in thechamber). As the CO2 vaporizes in the collector vile, it depositsshatter. In the third, optional step, called winterization, the CO2 oilis dissolved in ethanol (¾ ounce shatter dissolved in 400 ml ethanol).This mixture is then poured through a filter (such as a coffee filter)frozen for 48 hours, then warmed, filtered again, and then spun withheat to evaporate off the ethanol. The remaining resin contains acombination of THCA, THC and other cannabis compounds. The resin isheated for 60 minutes at 240° F. An HFLC test is run to determine theamount of THC and THCA present in the resin. 45 mg of the resincontaining 99% THC (as determined by HPLC) is dissolved in 1 ml of ethylalcohol. The dissolved resin is transferred and mixed with the solutionof curcumin-honey-ascorbic acid-melatonin solution. The solution isfiltered and sterilized using a 0.2-micron FES Nalgene filtration unitunder constant pressure in a sterilized environment. The filtered 30 mlsolution is transferred to and stored in an amber glass bottle that isautoclaved in an aseptic condition.

Animals, especially dogs and cats, can be treated according to theinvention. Dosage amounts, and serum levels of drug are the same asdisclosed above for human patients.

The term “about” as used herein is intended to allow for variations informulations of plus or minus 1 μg or 1 mg.

The transitional term “comprising” is synonymous with “including,”“containing,” or “characterized by,” is inclusive or open-ended and doesnot exclude additional, un-recited elements or method steps. Thetransitional phrase “consisting essentially of” is intended to embraceonly specified components or ingredients or steps and those that do notmaterially affect the basic and novel characteristics of the claimedinvention. In other words, elements or ingredients which materiallyaffect the essence of the invention are excluded by the phraseconsisting essentially of.

EXAMPLE 1: GENERAL METHOD OF PREPARATION

The following example sets out a method for the preparing theformulation. One dose of the liquid formulation is measured at 1 ml,comprising of 70% of water, 20% honey and 10% ethyl alcohol, 1.5 mg THC,1.5 mg melatonin, 1 mg turmeric, 1 mg ascorbic acid as an anti-oxidativeagent and 0.1% sodium benzoate as an anti-fungal agent. Food grade,solvents and carriers include among others DMSO and polyethylene glycol.Food grade anti-oxidative agents include among others carotenoids andtocopherols. Food grade agents with anti-fungal properties includeflavonoids among others.

The following is a list of ingredients for making 30m1 of theformulation:

Melatonin procured from Bulk Inc: 45 mg.Curcumin procured from Bulk Inc: 30 m.Ascorbic acid: 30 mgEthyl alcohol 200 proof: 3 ml.Water (USP grade RMBI): 21 ml

Honey (Kirkland—Costco): 6 ml

THC procured as “shatter”: 45 mgSodium benzoate USP, 33 mg

Weigh 30 mg of curcumin in a digital weighing machine and place it in aglass beaker containing 1 ml ethyl alcohol (200 proof). Add 21 ml ofwater to the curcumin alcohol mixture. Boil the water and curcuminmixture for 10 minutes on the hot plate and stir the mixture using amagnetic stirrer. After the mixture cools to room temperature, add 6 mlof honey to the curcumin mixture slowly with stirring. Weigh 30 mg ofascorbic acid and add to the curcumin-honey mixture. Weigh 45 mg ofmelatonin and dissolve it in a 1 ml of ethyl alcohol. Once melatonin iscompletely dissolved in alcohol, transfer the melatonin mixture tocurcum in-honey-ascorbic solution.

A further embodiments of Example 1 comprises of replacing turmeric withany of, or a combination of curcumin, nano-curcumin, and turmeric.

EXAMPLE 2

An Alzheimer's patient exhibiting slight anxiety and/or agitation isgiven 1 ml of the formulation set out in Example 1, in the morning on anempty stomach, prior to breakfast, and 1 ml prior to dinner in theevening. The patient exhibits reduced anxiety and agitation.

EXAMPLE 3

An advanced stage Alzheimer's patient exhibiting moderate to severeanxiety, sleep disorder and/or agitation is given 1 ml of theformulation three to four times a day, morning afternoon and evening,prior to meals. The patient exhibits reduced anxiety and agitationvastly improving the distress caused to the caregivers.

EXAMPLE 4

The formulation in Example 1, is supplemented with 50 mg of Cannabidiol(CBD) dissolved in 1 ml of ethyl alcohol and added to the overallsolution of Example 1. A moderate stage Parkinson's patient exhibitinglevodopa induced dyskinesia, stammering, anxiety, gait, sleep disorderand/or agitation is given 1 ml of the formulation of Example 4, three tofour times a day, morning afternoon and evening, prior to meals. Thepatient exhibits reduced symptoms.

EXAMPLE 5

The formulation of Example 4, without the THC component, is administeredthree times a day prior to meals to a moderate stage Parkinson's patientexhibiting levodopa induced dyskinesia, stammering, anxiety, gait, sleepdisorder and/or agitation. The patient exhibits reduced symptoms.

EXAMPLE 6

The formulation and dosing in Example 4, is administered to a patientwith moderate incontinence, two times a day, morning and evening, priorto meals. The patient exhibits reduced symptoms.

EXAMPLE 7

The formulation and dosing in Example 1, is administered, once a day,twice a day, to an individual exhibiting early signs of Alzheimer'sdisease, including plaques and tangles, as determined by a PET scan, asa prophylactic. The patient exhibits a slowdown in the buildup ofplaques and tangles.

EXAMPLE 8

The formulation and dosing in Example 1, without the THC component isadministered to a patient with mild symptoms of Alzheimer's disease twotimes a day, morning and evening, prior to meals as a prophylactic. Thepatient exhibits reduced symptoms.

EXAMPLE 9

To address the solubility and stability of THC in an alcohol/watermixture, the following active ingredients were combined in 30 mlsolution:

Turmeric: 30 mg Melatonin: 45 mg THC: 45 mg Honey: 6 ml Water: 21 ml

Ascorbic acid (THC antioxidant): 30 mgRutin (antifungal agent): 33 mgEthyl alcohol: 3 ml

Polysorbate-80

An nonionic emulsifier is preferably added to increase the solubility ofTHC and other active ingredients in the solution. Nonionic emulsifiersinclude lecithin from soy and sunflower, polysorbate 80 and vitamin ETPGS (d-α-tocopheryl polyethylene glycol 1000 succinate). Polysorbate 80is a nonionic surfactant and emulsifier derived from polyethoxylatedsorbitan and oleic acid.

Preferred emulsifiers are from 1-3% polysorbate-80, 2-5% vitamin E TPGSand a combination of 1% poltsorbate-80 and 1-2.5% Vitamin TPGS.

Sodium benzoate in Example 1 serves as an antifungal agent and naturalantifungal agents such as Rutin are also suitable. Natural antifungalagents with broad spectrum antifungal properties are more potent andless toxic compared to sodium benzoate.

Rutin, also called rutoside, quercetin-3-O-rutinoside and sophorin, is aglycoside combining the flavonol quercetin and the disacchariderutinose. It is a citrus flavonoid found in a wide variety of plantsincluding citrus fruit.

EXAMPLE 10

A preferred formulation in a 30 ml solution which maintains THC and theother components in a stable solution is as follows:

Curcumin: 0.05% Melatonin: 0.15% THC: 0.25% Honey: 20% Water: 65 to 55%

Ascorbic acid: 1%

Rutin: 0.05%

Ethyl alcohol: 12%

Polysorbate-80 (1%) and Vitamin E-TPGS (1 to 2.5%). CBD: 0.25% to 5%

It is preferred to use 20-30% honey and/or 12% alcohol to increase thesolubility of THC. The use of 1% of an antioxidant such as ascorbic acidis also preferred to counter degradation of THC when exposed toatmospheric oxygen.

While this invention has been described as having preferred sequences,ranges, ratios, steps, order of steps, materials, structures, symbols,indica, sativa, hemp, graphics, color scheme(s), shapes, configurations,features, components, or designs, it is understood that it is capable offurther modifications, uses and/or adaptations of the inventionfollowing in general the principle of the invention, and including suchdepartures from the present disclosure as those come within the known orcustomary practice in the art to which the invention pertains, and asmay be applied to the central features hereinbefore set forth, and fallwithin the scope of the invention and of the limits of the claimsappended hereto or presented later. The invention, therefore, is notlimited to the preferred embodiment(s) shown/described herein.

1.-19. (canceled)
 20. Formulation for treating a central nervous system(CNS) disorder in a human or animal, wherein said formulation comprisesa combination of (a) cannabis compound or compounds and (b) melatoninand/or curcumin; wherein said combination is tetrahydrocannabinol (THC),cannabidiol (CBD), melatonin, and curcumin; or THC, melatonin, andcurcumin; or THC, CBD, and melatonin; or CBD and melatonin in thefollowing dose amounts per 70-Kg patient (i) THC from about 14 μg toabout 10.0 mg, (ii) CBD from about 14 μg to about 200 mg, (iii)melatonin from about 14 μg to about 20.0 mg, and (iv) curcumin fromabout 0.35 mg to about 500 mg.
 21. Formulation for treating a centralnervous system (CNS) disorder in a human or animal, wherein saidformulation comprises a combination of (a) cannabis compound orcompounds and (b) melatonin and/or curcumin; wherein said combination istetrahydrocannabinol (THC), cannabidiol (CBD), melatonin, and curcumin;or THC and CBD in the following dose amounts per 70-Kg patient: (i) THCfrom about 14 μg to about 2.0 mg, (ii) CBD from about 14 μg to about 200mg, (iii) melatonin from about 14 μg to about 20.0 mg, and (iv) curcuminfrom about 0.35 mg to about 500 mg.
 22. Formulation of claim 20, whereinsaid THC is selected from the group consisting of organic THC, syntheticTHC, Dronabinol, Δ9-THC, and THC acid.
 23. Formulation of claim 20,wherein said dose amount of melatonin per 70-Kg patient is from about0.7 mg to about 10 mg.
 24. Formulation of claim 20, wherein said doseamount of melatonin per 70-Kg patient is from about 14 μg to about 1.4mg.
 25. Formulation of claim 20, wherein said dose amount of melatoninper 70-Kg patient is from about 1.4 mg to about 20.0 mg.
 26. Formulationof claim 25, wherein said curcumin is selected from the group consistingof turmeric, organic turmeric, synthetic curcumin, synthetic turmeric,organic curcumin and/or curcumin enhanced for better absorption, taste,and/or bioavailability, and mixtures thereof.
 27. Formulation of claim20, wherein said formulation is in a liquid carrier and furthercomprises a non-ionic emulsifier in an amount sufficient to maintainstability and solubility.
 28. Formulation of claim 27, wherein saidnon-ionic emulsifier is selected from the group consisting of soylecithin, sunflower lecithin, Tween 80 (polysorbate 80), and vitamin ETPGS (d-α

ocopheryl polyethylene glycol 1000 succinate).
 29. Formulation of claim20, wherein said formulation further comprises an anti-fungal agent. 30.Formulation of claim 29, wherein said anti-fungal agent is sodiumbenzoate or rutin.
 31. Method for treating a central nervous system(CNS) disorder in a human or animal, which method comprisesadministering to a patient suffering therefrom (a) tetrahydrocannabinol(THC), cannabidiol (CBD), melatonin, and curcumin; or (b) THC,melatonin, and curcumin; or (c) THC, CBD, and melatonin; or (d) CBD andmelatonin in the following dose amounts per 70-Kg patient: (i) THC fromabout 14 μg to about 10.0 mg, (ii) CBD from about 14 μg to about 200 mg,(iii) melatonin from about 1.4 mg to about 20.0 mg, and (iv) curcuminfrom about 0.35 mg to about 500 mg.
 32. Method for treating a centralnervous system (CNS) disorder in a human or animal, which methodcomprises administering to a patient suffering therefrom cannabiscompounds comprising (i) tetrahydrocannabinol (THC) in an ultra-low doseamount per 70-Kg patient of from about 14 μg to about 2.0 mg and (ii)cannabidiol (CBD) in a dose amount per 70-Kg patient of from about 14 μgto about 200 mg.